Method and apparatus for administering analgesics, and method for making same device

ABSTRACT

A device and method is disclosed for continuously administering an analgesic to the neuraxis of an organism. The device comprises a polymeric matrix body loaded with the analgesic. The body is implanted in the neuraxis where the analgesic diffuses into the neuraxis.

This application is a continuation of application(s) Ser. No. 08/386,853filed on Feb. 10, 1995, now abandoned.

TECHNICAL FIELD

This invention relates to a device and method for administeringanalgesics to the neuraxis of an organism. More specifically, thisinvention relates to the long term release of an analgesic from abiocompatible polymeric matrix device implanted into the central nervoussystem of a human patient or other warm blooded animal.

BACKGROUND OF THE INVENTION

Constant or chronic pain is a significant medical problem, for examplein terminal cancer patients. Many of the drugs, such as the opioid classof analgesics, used to treat severe chronic pain act on receptors foundin the neuraxis. By "neuraxis" as used herein is meant any region oftissue that comprises the spinal cord, brain or central nervous system.

The current regimen for treatment of these patients is systemicadministration of relatively high doses of analgesics by for exampleoral, subcutaneous, intramuscular, intravenous and related routes on adaily or continuous basis. Oral administration of an analgesic isproblematic because the patient experiences high systemic concentrationof drug at the time of ingestion followed by a gradual decrease insystemic concentration of the drug until the next dose is ingested.Other methods of systemic administration are problematic because theymay be invasive, for example placement of an intravenous catheter forcontinuous administration of the analgesic. In either case, however, theanalgesic is distributed equally throughout the body after beingadministered systemically and diffuses across the blood-brain barrierinto the neuraxis to its central site of action, blocking pain messagesto the brain. The cost for treating these patients is high from ahospital care as well as from a pharmaceutical standpoint since manypatients must be maintained in the hospital to continue their paintreatment regimen of high doses of the analgesic. Furthermore, sideeffects related to the systemic administration of high doses of, forexample, opioids include sedation, respiratory depression, nausea,constipation and vomiting. These side effects are well documented inproduct labeling and the literature and detract greatly from the alreadycompromised quality of life of these patients.

More recently, transdermal patches have been developed as a means forefficiently delivering analgesics to patients on a continuous basis. Apatch is loaded with an analgesic such as fentanyl and is attached tothe patient's skin by means of typically an adhesive. The analgesicdiffuses out of the patch and crosses the patient's skin, where it isabsorbed by the body. Patients may be required to wear a number ofpatches to obtain adequate therapeutic response, as the analgesic siteof action is in the neuraxis. While less invasive than otheradministration techniques listed above, systemic side effects resultingfrom high levels of analgesic in the body are still a significantmedical problem and continue to compromise patient quality of life.

Alternatively, spinal administration (intrathecal or epidural) ofcentrally acting analgesics via an externalized spinal catheter, aspinal catheter connected to an external infusion pump, a spinalcatheter connected to a fully implanted infusion pump and other relatedsystems has been shown to be therapeutically effective for the treatmentof chronic pain. To reduce systemic side effects caused by relativelyhigh dosage systemic delivery, direct spinal delivery of the analgesicis preferred. In this way, drug is delivered in a concentrated mannerand at low doses to its specific site of action on receptors in theneuraxis, minimizing systemic side effects as outlined above. Spinalcatheter placement and infusion pump use, while shown to be highlyeffective, represent a therapy alternative that is relatively expensiveand invasive to implant. These therapies also present with risk ofspinal infection such as meningitis since the blood-brain barrier hasbeen compromised and drug is delivered to the neuraxis from an externalsource such as a drug pump.

Recent research has also demonstrated that living cells that producenatural analgesics can be encapsulated into a silicone sheath andimplanted into the central nervous system. It has not been establishedwhether these cells produce therapeutic quantities of analgesics whilein vivo or how long the encapsulated cells will remain viable. Doses ofanalgesic that the cells produce in many instances can not be controlledand external stimuli, for example nicotine, may change cell viabilityparameters. Finally, potential for infection in the neuraxis if one ofthese modules were to rupture has not been characterized.

The present invention provides an alternative means for achievingcontinuous central nervous system administration of an analgesic intothe neuraxis via intraventricular, epidural, intrathecal and relatedroutes for those suffering chronic pain and is directed to solving oneor more of the problems noted above. The invention comprises ananalgesic carrying device and its method of use, including implantation,which releases the analgesic in a continuous and sustained-releasemanner. The device consists of a biocompatible polymer matrix bodyloaded with an analgesic such that a slow, preferably constant releaseof the analgesic is provided. The polymer matrix substrate may beconstructed of any of a number of biostable or biodegradable polymersthat act as the carrier matrix for the analgesic. Ideally, therapeuticlevels of the analgesic will be delivered over the long term, i.e., onemonth to one year. Two preferred analgesics are fentanyl and sufentanil,opioids about 100 to 500 and 1000 to 5000 times, respectively, morepotent than morphine. Preferably the method of the invention administersthe analgesic intraventricularly, intrathecally, epidurally, or by otherrelated routes to the neuraxis. The intrathecal route of administrationis preferred.

SUMMARY OF THE INVENTION

With this invention it is recognized for the first time that increasedcost-effectiveness and simplicity of the administration of analgesicsdirectly to the central nervous system, i.e., neuraxially, may beaccomplished by means of a polymer matrix body loaded with an analgesicand made available for diffusion from the matrix into the biologicneuraxial environment.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a view of a side matrix body made from a biocompatible polymercontaining analgesic in the interstices thereof.

FIGS. 1a, 1b and 1c show alternate configurations.

FIG. 2 is a view of a preferred shape of the matrix body for retrievalpurposes.

FIG. 3 is a schematic showing the spinal column and demonstrating thelumbar implantation of an analgesic loaded matrix body by ejection ofsame from a needle.

FIG. 4 is a more detailed showing of the matrix body in the needle ofFIG. 3 and a method of delivery of same into the body environment.

FIG. 5 is a graph showing examples of fentanyl elution from polyurethaneover time as the percent of the total fentanyl available.

FIG. 6 is a graph showing fentanyl elution from silicone over time asthe percent of the total fentanyl available.

FIG. 7 is a graph showing sample matrices in terms of effective dose inmicrograms per day as administered from a matrix body according to theinvention.

FIGS. 8, 9 and 10 are graphs showing the amount of fentanyl delivered asa percent of the total amount of fentanyl bonded with several samplematrix geometries.

DETAILED DESCRIPTION OF THE INVENTION

Turning now to the drawings, which disclose examples of various drugdelivery devices and methods according to the invention, one embodimentof the device is indicated in FIG. 1 at 10. Device 10 comprises apolymeric matrix body 12 made of a biostable or biodegradable polymerloaded with an analgesic such as fentanyl. Device 10 can be used for thecontinuous administration of the analgesic to the neuraxis of an animalbody. Device 10 delivers an analgesic by elution of the analgesic fromthe matrix polymer body 12 in a fluid environment at a gradual mannerwith the drug being delivered at a controlled and continuous rate over aprolonged period of time. The analgesic elutes from the matrix body 12due to the permeation of water and lipids from the interstitial fluidthrough the polymer matrix. This permeation solubilizes the analgesic toallow release from the matrix body 12. Various factors such as geometry,size, material, and pore size all affect permeability of the polymermatrix body 12 and resultant elution rates of the analgesic to theneuraxis.

FIG. 1a shows a cylinder configuration for body 12a of device 10 withrounded ends for easing placement and retrieval. FIG. 1b shows acylinder configuration for body 12b of device 10 formed from a rolled-upsheet of polymer material. FIG. 1c shows a cylinder configuration forbody 12c of device 10 in the form of a hollow tube, containing aquantity of an analgesic 16. The analgesic 16 may be dispersed withinthe polymer. Many other configurations will be apparent to thosefamiliar with this art.

Attached to body 12 by any suitable means of connection such as adhesiveor fusion is a tether 14 of such a length as to allow for retrieval ofdevice 10 at any time following implantation thereof into the neuraxisregion of an animal body. The tether 14 may be of any knownbiocompatible material such as nylon as is generally used in surgery.

FIG. 2 illustrates a preferred configuration of body 12 in which theproximal end thereof, i.e., the end to which tether 14 is attached istapered for facilitating retrieval.

The polymer utilized for making up the matrix body 12 of device 10 maybe any suitable biocompatible polymer, whether biostable orbiodegradable.

Biostable polymers that may be utilized include silicone, polyurethane,polyether urethane, polyether urethane urea, polyamide, polyacetal,polyester, poly ethylene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or "Teflon®"), styrene butadiene rubber,polyethylene, polypropylene, polyphenylene oxide-polystyrene,poly-a-chloro-p-xylene, polymethylpentene, polysulfone and other relatedbiostable polymers. Presently, polyurethane is a preferred biostablepolymeric matrix material for body 12, but many of the above listedpolymers may be useful for this application.

Biodegradable polymers that may be utilized include polyanhydrides,cyclodestrans, poly lactic-glycolic acid, polyorthoesters, n-vinylalcohol, polyethylene oxide/polyethylene terephthalate, polyglycolicacid, polylactic acid and other related bioabsorbable polymers. In theevent a biodegradable polymer is used as the matrix body 12, the tether14 may or may not be utilized since permanent implantation may beacceptable.

The analgesic 16 loaded into the polymer matrix body 12 may be from oneof any number of classes of analgesics that have been shown to actcentrally on specific pain receptors in the neuraxis. Potential drugclasses include analgesics, typically called opioids, that act on opioidpain receptors. Examples of such opioid analgesics are morphine,fentanyl, sufentanil, alfentanil, hydromorphone, meperidine, methadone,buprenorphine, DADL, butorphanol and related opioids. Other potentialdrug classes include analgesics that act on non-opioid pain receptors.One such group of analgesics that act on non-opioid pain receptors arealpha-2 adrenergic receptor agonists such as clonidine, tizanidine,ST-91, medetomidine, dexmedetomidine and related alpha-2 adrenergicagonists. Another group of analgesics are NMDA receptor antagonists suchas dexmethorphan, Ifenprodil, MK-801 and related NMDA antagonists. Yetanother group of analgesics are somatostatin analogs such as Octreotide,Sandostatin, Vapreotide, Lanreotide and related somatostatin analogs.Finally, other analgesics may be used that act on non-opioid painreceptors such as ketorolac, super oxide dismutase, baclofen,calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin,omega-conopeptides and related non-opioid analgesics. The list is notintended to be complete, but rather to demonstrate the broad potentialand feasibility of the invention to act on a number of central painreceptors, even though not all agents may be readily used to construct adevice of clinically viable size. The preferred analgesic presently isthe opioid fentanyl that is about 100 to 500 times more potent thanmorphine and is well characterized in the neuraxis or alternativelysufentanil that is about 1000 to 5000 times more potent than morphine.

Analgesic Loading

The analgesic 16 may be loaded into the polymer matrix body 12 by anumber of techniques. The choice of loading technique for a particularanalgesic/polymer matrix/device geometry will be dependent on a numberof factors including drug/polymer/solvent compatibility, desired finalconcentration of analgesic 16 in the polymer matrix body 12, simplicityof the process, desired final geometry of the device 10 and preferredelution characteristics of the completed device 10. As examples, a fewloading technique options are listed as follows. The list is notintended to be complete or limiting, but rather to serve as exampleswell understood by anyone skilled in the art.

The analgesic 16 may be loaded into the polymer body 12 by means ofdispersion loading. Dispersion loading is the technique of loading apowdered substance into a polymer by stir-mixing it into the polymerprecure or solution to make a dispersion of the two materials. Thepowder is not dissolved by the polymer solution in dispersion loading.The polymer is solidified by curing or solvent evaporation and ahomogeneous blend of analgesic 16 in the polymer is achieved. Theanalgesic 16 has not reacted with the polymer, but rather is dispersedwithin the interstitial spaces of the cured polymer. The concentrationof drug that can be loaded into the polymer is limited only by thephysical integrity of the resulting polymer matrix body 12. Dispersionmixing is a standard technique for loading dexamethasone into polymericlead tips to create steroid eluting leads.

The dispersion loading method is the preferred method of combininganalgesic 16 with the polymeric matrix body 12 because the method allowsfor a fairly high percentage of analgesic 16 to be added to the polymerto form matrix body 12. The percentage of analgesic 16 added to thepolymer to form matrix body 12 is preferably from 10% to 80% by weight.This percentage has been found to maintain the integrity of the polymersubstrate in body 12. A higher loading concentration of analgesic 16allows for the design of a smaller device 10 for clinical use andplacement in the neuraxis.

The dispersion loading method also allows the body 12 to be formed intooptimal geometries prior to cure of the polymer or for body 12 to beextruded as a tube or other geometry. Finally, solvent compatibilitybetween the polymer of body 12 and the analgesic 16 is not a factor.

Alternatively, solvent swelling can be used to combine the analgesic 16with the polymeric matrix body 12. This method is particularly usefulwhere a preformed polymer body 12 is introduced into a solution of theanalgesic 16 in a solvent that acts as a swelling agent for the polymerbody 12. The body 12, while swelling, absorbs the solvent along with thedissolved analgesic 16 until a steady state is achieved. The polymerbody 12 is then allowed to dry with the solvent evaporating from thesample and the analgesic 16 left behind in the body 12. As the body 12dries, it returns from its swelled state to its original geometry andsize. Solubility of the analgesic 16 in the solution limits the possibleconcentration of drug that can be introduced by this technique. Even so,the technique is well known and has been used successfully to loadantimicrobials into polymer matrices. (See, for example, U.S. Pat. No.4,917,686).

Solution loading is similar to dispersion loading except that theanalgesic 16 or drug must be soluble in the polymer solvent. The curedpolymer body 12 then includes the dissolved analgesic 16 or drug in itsmatrix.

Finally, the method of reservoir loading may be used to combine theanalgesic 16 with the body 12. This method comprises loading pure drugor analgesic 16 inside a hollow tube and sealing the ends of the tube toform the body 12. The analgesic 16 then diffuses through the polymertubing wall of body 12.

Although the configuration of the device 10 may be varied including forexample rods, rolled up sheets, buttons, discs, tubes, microspheres andfibers, the presently preferred configuration is a small tube or rod ofpolymer the size and shape of a grain of rice which may be readilyintroduced into the intrathecal space via a 14 gauge needle. Finalproduct configuration may be fabricated by any of the foregoingtechniques.

More specifically, small device sizes typically less than 0.10 inches indiameter are contemplated for the preferred method of administrationcomprising the simple lumbar puncture technique. This technique isillustrated with reference to FIG. 3 wherein a needle 20, preferablyfourteen (14) gauge or smaller in size is inserted between the vertebrae30 into the epidural space 32 or the intrathecal space 36 in the knownlumbar puncture technique. The arachnoid layer is shown at 34 and thespinal cord at 38.

Needle 20, as is best shown in FIG. 4, contains the device 10 to beimplanted. Needle 20 also contains a pusher rod or cylinder 22 that isused to eject device 10 from needle 20 for implantation. Preferably, asshown, pusher rod or cylinder 22 is hollow so as to readily accommodatetether 14 whereupon removal of needle 20 and pusher rod 22 leaves theimplanted device 10 in place with the tether 14 extending therefrom.Tether 14 preferably extends away from the body 10 and terminates underthe skin but outside the spinal cord so that tether 14 is easilyaccessible when retrieval is desired. To retrieve body 12, the needle 20is simply inserted over the tether 14 and moved to body 12. Tether 14 isthen used to draw the body 12 into the needle 20 and the body 12 isremoved with the needle 20.

Alternatively, the combined analgesic/polymer matrix body 12 may beattached to the end of a standard spinal catheter by any suitable meanssuch that the outer diameter of the device 10 equals the outer diameterof the catheter. The device/catheter system may then be introduced intothe desired location in the spinal column by the standard lumbarpuncture technique using standard needles and procedures. The system maybe retrieved in the same manner as a standard spinal catheter isretrieved today as is well understood by those skilled in the art.

Preferably, implantation of the device 10 will occur in the intrathecalspace as opposed to the epidural space. This is because less analgesic16 is required for effective control of chronic pain when device 10 isintroduced to the intrathecal space as compared to the epidural space.As already indicated, the techniques described herein may also be usedfor implantation of device 10 into a brain ventricle.

Table I shown hereinbelow provides an example of the device sizerequirements for providing a minimal six-month dose of fentanyl toaccomplish chronic pain control in a more or less typical situationinvolving intrathecal administration.

                  TABLE I                                                         ______________________________________                                        DRUG NEEDS                                                                      Intrathecal fentanyl dosage: 0.1 to 0.3 mg/day                                Using minimal dose for 6 months                                               Assuming polymer and drug densities ≅ 1 g/cm.sup.3 or 1           mg/mm.sup.3                                                                     0.1 mg/day × 180 days × 1 mm.sup.3 /mg = 18.0 mm.sup.3          fentanyl to be delivered                                                        DEVICE SIZE                                                                   Assume 20% loading, and 50% delivery in 6 months                               -                                                                          1  STR1##                                                                        - Device of volume 180.0 mm.sup.3 or 0.18 cm.sup.3 :                         Cube, 0.56 cm on-a-side                                                       Cylinder, D = 1.8 mm, L = 70 mm (2.8 in)                                    ______________________________________                                    

DETAILED DESCRIPTION OF EXAMPLES

The following examples are set forth as representative of the spirit ofthe present invention. These examples are not to be construed aslimiting the scope of the invention, as these and other functionallyequivalent methods and devices will be readily apparent to those skilledin the art. Studies to date have focused on developing andcharacterizing a feasible polymer matrix substrate for body 12 that willelute analgesic 16 continuously and over the long term, i.e., one monthto one year. In patients or animals, near zero order release kineticsfor the duration of the implant are preferred because stable drugconcentrations may be maintained in the neuraxis. Zero order releasekinetics means that over time, the amount of drug released by thepolymer matrix remains at a relatively constant rate. For example, foran implant having a useful duration of several months, with zero orderrelease kinetics, the amount of drug released from the polymer matrix onday 30 will be the same as the amount of drug released from the matrixon day 5. Finally, the analgesic loaded polymer matrix body 12 must besterilizable, biocompatible and of a geometry and size that is easilyimplantable and removable in the neuraxis.

For the following examples, fentanyl citrate was chosen as the preferredanalgesic 16 because it has a centrally acting mode of effect, is 100times more potent than morphine, and is a stable and well characterizedopioid analgesic. Fentanyl citrate powder was purchased from USPC Inc.,Rockville, Md. Polymer substrate materials tested included medical gradesilicone purchased from Rehau Corp., Leesburg, Va., Trade name RaumedicSI2000) and Pellethane brand polyurethane of durometer 80A purchasedfrom Dow Chemical, Midland, Mich. Polyurethane adhesive was prepared byheat press molding Pellethane pellets into film and dissolving the filmin dimethyl acetamide (DMAC) solvent.

Initial studies identified a polymer matrix, developed an effectivetechnique for loading fentanyl into the matrix as discussed earlier, andcompared the in vitro release kinetics of fentanyl from variousmatrices. Also described are studies comparing the effect of fentanylrelease as a function of polymer type, matrix porosity, drugconcentration and device shape. All samples were placed into a phosphatebuffered saline solution and were maintained at 37 C. Eluate sampleswere pulled at various time points for analysis by standard highpressure liquid chromatography (HPLC) techniques, with samples beingcompared against a standard fentanyl concentration curve. Examples arediscussed as follows:

EXAMPLE 1

This example evaluates the release kinetics of the analgesic fentanylfrom relatively nonporous polyurethane matrix samples 1 and 2 over time.Data is shown in FIG. 5. The samples 1 and 2 are also compared toalternative silicone carrier matrix samples 3 and 4 shown in FIG. 6 anddiscussed in Example 2.

Polyurethane samples 1 and 2 in FIG. 5 were prepared by the dispersiontechnique discussed earlier and well understood by those skilled in theart. Polyurethane used was Pellethane 80A. Samples 1 and 2 were loadedwith a 10% fentanyl powder and were prepared in a film configurationapproximately three quarter inches long by one quarter inch wide by0.015 inches thick. Samples 1 and 2 were placed in standard phosphatebuffered solution (PBS) and allowed to elute drug for 60 days at 37C.

FIG. 5 shows the amount of fentanyl delivered as a percent of the totalamount of fentanyl loaded into the sample, i.e., cumulative elution.Release kinetics are nearly zero order, with the amount of drug beingdelivered on day 50 nearly equal to the amount of drug being deliveredon day 10.

FIG. 7 presents the data for the first 28 days as micrograms per day offentanyl delivered from the matrix by samples 1 and 2. Following a firstday bolus, the samples both eluted drug at approximately 30 microgramsper day, approximately one third to one tenth the effective intrathecaldose required for human clinical use. Results for both samples wereconsistent for each time point as well as over time.

EXAMPLE 2

This example evaluates the release kinetics of the analgesic fentanylfrom silicone matrix samples 3 and 4 over time. The samples 3 and 4 werealso compared to alternative polyurethane carrier material samples 1 and2 as described in Example 1 above.

Silicone samples 3 and 4 in FIG. 6 were prepared by the dispersiontechnique discussed earlier and well understood by those skilled in theart. Samples 3 and 4 were loaded with a 10% fentanyl powder and wereprepared in a film configuration approximately one inch long by one halfinch wide by 0.020 inches thick. Samples were placed in standardphosphate buffered solution (PBS) and allowed to elute drug for 60 daysat 37 C.

FIG. 6 shows the amount of fentanyl delivered as a percent of theinitial total amount of fentanyl loaded into the sample, i.e.,cumulative elution. In contrast to the polyurethane samples 1 and 2,silicone samples 3 and 4 provide a bolus release of fentanyl on day onefollowed by decreasing drug release thereafter. Results of both siliconesamples 3 and 4 were consistent for each time point as well as overtime.

EXAMPLE 3

This example compares the effect of different fentanyl loadingconcentrations on release kinetics using a relatively nonporouspolyurethane film.

Polyurethane samples 5 and 6 in FIG. 8 were prepared by the dispersiontechnique discussed earlier. Polyurethane used was Pellethane 80A.Samples 5 and 6 were loaded with 10% fentanyl powder and 25% fentanylpowder, respectively by weight and prepared in a film configurationapproximately one quarter inch wide by one quarter inch long by 0.01inches thick. Samples 5 and 6 were placed in standard phosphate bufferedsolution (PBS) and allowed to elute drug for 60 days at 37 C.

FIG. 8 shows the cumulative amount of fentanyl delivered as a percent ofthe total amount of fentanyl loaded into the samples. The graph showsthat the higher the concentration of fentanyl loaded into the sample,the greater the release rate of the analgesic. The 25% fentanyl loadedsample 6 exhibits nearly zero order release kinetics over the first 30days, with drug elution rates tailing off from day 30 to day 60.

EXAMPLE 4

This example compares release kinetics of a number of fentanyl loadingconcentrations from a relatively porous polyurethane pellet.

Polyurethane samples 7, 8 and 9 in FIG. 9 were prepared by thedispersion technique discussed earlier. Polyurethane used was Pellethane80A as in the previous examples, but the polymer samples were allowed tocure in a high humidity environment rather than in a vacuum. Casting thepolyurethane film in a high humidity environment created a phaseinversion allowing the polyurethane to precipitate and cure in arelatively porous fashion. Samples 7, 8 and 9 were loaded with 10%fentanyl powder, 25% fentanyl powder, and 40% fentanyl powder,respectively by weight, and were prepared as pellets approximately onehalf inch long by 0.05 inches wide by 0.03 inches thick. The sampleswere placed in standard phosphate buffered solution and allowed to elutedrug for 60 days at 37 C.

FIG. 9 shows the amount of fentanyl delivered as a percent of the totalamount of fentanyl loaded into the samples. The graph shows that thehigher the concentration of drug loaded into the sample, the greater therelease rate. All samples suggest a large analgesic bolus is deliveredon day one, followed by decreasing analgesic elution thereafter.

EXAMPLE 5

This example compares effects of geometry of a sample on releasekinetics. Polymer matrix material and fentanyl loading concentration areheld constant.

Polyurethane samples 10 and 11 in FIG. 10 were prepared by thedispersion technique discussed earlier. Polyurethane used was Pellethane80A. Samples 10 and 11 ere loaded with 10% fentanyl powder and wereprepared as a film and a tube, respectively. Tubing sample 11 wasprepared approximately one eighth inches in outer diameter with a wallthickness of 0.005 inches and one quarter inch in length. Film sample 10was prepared approximately one quarter inch wide by one quarter inchlong by 0.01 inches thick. Samples 10 and 11 were placed in standardphosphate buffered solution and allowed to elute drug for 60 days at37C.

FIG. 10 shows the amount of fentanyl delivered as a percent of the totalamount of fentanyl loaded into the samples. The samples provideconsistent drug release over 60 days, with the tube geometry releasing agreater amount of fentanyl and at a greater rate.

The above Examples and disclosure are intended to be illustrative andnot exhaustive. These examples and description will suggest manyvariations and alternatives to one of ordinary skill in this art. Allthese alternatives and variations are intended to be included within thescope of the attached claims. Those familiar with the art may recognizeother equivalents to the specific embodiments described herein whichequivalents are also intended to be encompassed by the claims attachedhereto. The examples demonstrate that an optimum geometry and analgesicloading may be prepared to allow for nearly zero order release kinetics(straight line) of therapeutic amounts of an analgesic over a period oftime, for example one month to one year.

What is claimed is as follows:
 1. A method for administering ananalgesic to an animal comprising the steps of:implanting, in the regionof the spinal column of the animal, a biostable polymeric matrix bodyloaded with the analgesic wherein said analgesic is only released fromsaid biostable polymeric matrix, and releasing an efficacious amount ofthe analgesic over time to the animal from the matrix body.
 2. Themethod of claim 1 wherein the step of releasing includes eluting theanalgesic at a nearly constant rate over the useful life of theanalgesic.
 3. The method of claim 1 wherein the analgesic released inthe step of releasing is an analgesic that acts on opioid painreceptors.
 4. The method of claim 3 wherein the analgesic that acts onopioid pain receptors is selected from the group consisting of morphine,fentanyl, sufentanil, alfentanil, hydromorphone, meperidine, methadone,buprenorphine, DADL and butorphanol.
 5. The method of claim 1 whereinthe analgesic released in the step of releasing is an analgesic thatacts on opiod pain receptors.
 6. The method of claim 5 wherein theanalgesic that acts on non-opioid pain receptors is selected from thegroup consisting of ketorolac, super oxide dismutase, baclofen,calcitonin, serotonin, vasoactive intestinal polypeptide, bombesin andomega-conopeptide.
 7. The method of claim 1 wherein the analgesicreleased in the step of releasing is an alpha-2 adrenergic agonist. 8.The method of claim 7 wherein the alpha-2 adrenergic agonist is selectedfrom the group consisting of clonidine, tizanidine, ST-91, medetomidineand dexmedetomidine.
 9. The method of claim 5 wherein the analgesic thatacts on non-opioid pain receptors is an NMDA receptor antagonist. 10.The method of claim 9 wherein the NMDA receptor antagonist is selectedfrom the group consisting of dexmethorphan, Ifenprodil and MK-801. 11.The method of claim 5 wherein the analgesic that acts on non-opioid painreceptors is a somatostatin analog.
 12. The method of claim 11 whereinthe somatostatin analog is selected from the group consisting ofOctreotide, Sandostatin, Vapreotide and Lanreotide.
 13. The method ofclaim 1 wherein the step of implanting a biostable polymeric matrix bodyloaded with an analgesic includes implanting a polymeric matrix bodymade of a material chosen from the group consisting of silicone,polyurethane, polyether urethane, polyether urethane urea, polyamide,polyacetal, polyester, poly(ethylene-chlorotrifluoroethylene), polytetrafluoroethylene (Teflon), styrene butadiene rubber, polyethylene,polypropylene, polyphenylene oxide-polystyrene, poly-a-chloro-p-xylene,polymethylpentene and polysulfone.
 14. The method of claim 1 furthercomprising the step of configuring the body for ease of introduction toand removal from the spinal column of an animal prior to performing thestep of implanting a biostable polymeric matrix body.
 15. The method ofclaim 1 further comprising the step of attaching a tether to the matrixbody to facilitate removal of the matrix body from the animal, and,wherein the step of implanting a biostable polymeric matrix bodyincludes implanting the matrix body so that the tether extends away fromthe polymeric matrix body and terminates outside the spinal column ofthe animal so that the tether is easily accessible when retrieval isdesired.
 16. The method of claim 1 wherein the step of implanting abiostable polymeric matrix body loaded with the analgesic includes thesteps of:placing the matrix body in a hollow needle; and pushing thematrix body through and out of the needle with a pusher rod.
 17. Themethod of claim 1 wherein the step of implanting a biostable polymericmatrix body loaded with the analgesic includes the steps of:attachingthe matrix body to the distal end of a catheter; and introducing thedistal end of the catheter into the spinal column.
 18. The method ofclaim 1 wherein the step of implanting a biostable polymeric matrix bodyfurther comprises the step of implanting a biostable polymeric matrixbody in the spinal column using a lumbar puncture technique.
 19. Themethod of claim 1 wherein the matrix body is implanted in theintrathecal space.
 20. The method of claim 1 wherein the matrix body isimplanted in the epidural space.
 21. The method of claim 1 wherein thestep of implanting a biostable polymeric matrix body loaded with theanalgesic includes the step of placing the analgesic in the matrix bodyin an amount of about 10% to 80% by weight.
 22. A method foradministering an analgesic to an animal comprising the steps of:making abiostable polymeric matrix body loaded with an analgesic, the matrixbody configured for ease of introduction to and removal from the spinalcolumn of the animal; implanting, in the region of the spinal column ofthe animal; and diffusing an efficacious amount of the analgesic overtime to the animal from the matrix body, wherein the analgesic isdiffused at a sustained rate over the useful life of the analgesic. 23.The method of claim 22 wherein the step of making a biostable polymericmatrix body loaded with an analgesic includes the step of loading theanalgesic into the matrix body by means of dispersion loading.
 24. Themethod of claim 22 wherein the step of making a biostable polymericmatrix body loaded with an analgesic includes the step of loading theanalgesic into the matrix body by means of solvent swelling.
 25. Themethod of claim 22 wherein the step of making a biostable polymericmatrix body loaded with an analgesic includes the step of loading theanalgesic into the matrix body by means of solution loading.
 26. Themethod of claim 22 wherein the step of making a biostable polymericmatrix body loaded with an analgesic includes the step of loading theanalgesic into the matrix body by means of reservoir loading.
 27. Amethod for making a device to be implanted in the region of the neuraxisof an animal, the device to diffuse analgesic into the region of theneuraxis of the animal at a substantially sustained rate over the lifeof the device, the method comprising the steps of:forming a polymericprecure of a biostable material; stir-mixing a powder mixture ofanalgesic into the polymeric precure to make a dispersion of thepolymeric precure and the analgesic whereby the powder mixture ofanalgesic is not dissolved by the polymeric precure; forming thedispersion into a desired configuration; and solidifying the dispersionof the analgesic and polymeric precure.
 28. The method of claim 27wherein the step of solidifying the dispersion is accomplished by curingthe dispersion.
 29. A method for making a device to be implanted in theregion of the neuraxis of an animal, the device to diffuse analgesicinto the region of the neuraxis of the animal at a substantiallysustained rate over the life of the device, the method comprising thesteps of:a. forming a polymeric substance of a material into a desiredconfiguration; b. forming a mixture of a solvent and an analgesic; c.introducing the polymeric substance formed in step a. into the mixtureformed in step b.; d. allowing the polymeric substance formed in step a.to absorb the mixture formed in step b. during the performance of stepc.; e. removing the polymeric substance and absorbed mixture of solventand analgesic from the mixture of solvent and analgesic after step d.has been performed; and f. drying the polymeric substance and solventand analgesic mixture removed in step e. so that the solvent evaporatesfrom the polymeric substance and solvent and analgesic mixture therebyleaving only the analgesic absorbed in the polymeric substance.
 30. Amethod for making a device to be implanted in the region of the spinalcolumn of an animal, the device to diffuse analgesic into the region ofthe spinal column of the animal at a substantially sustained rate overthe life of the device, the method comprising the steps of:a. forming apolymeric substance of a biostable material into a hollow tube, thepolymeric material capable of allowing a selected analgesic to diffusetherethrough; b. loading the selected analgesic into the hollow tubeformed in step a.; and c. sealing the ends of the tube formed in step a.with the selected analgesic inside.
 31. A device for administering ananalgesic to an animal at a sustained rate over a period of time, thedevice being shaped, sized and adapted for administering the analgesicinto the region of the spinal column of the animal, the devicecomprising:a biostable polymeric matrix body; and an analgesic, loadedinto the matrix body, the analgesic available for diffusion onlytherefrom into the region of the spinal column of the animal.
 32. Thedevice of claim 31 wherein the analgesic is loaded into the matrix bodyby means of dispersion loading.
 33. The device of claim 31 wherein theanalgesic is loaded into the matrix body by means of solvent swelling.34. The device of claim 31 wherein the analgesic is loaded into thematrix body by means of solution loading.
 35. The device of claim 31wherein the analgesic is loaded into the matrix body by means ofreservoir loading.
 36. The device of claim 31 wherein the matrix body isconfigured as a rod.
 37. The device of claim 34 wherein the matrix bodyhas a diameter of less than about 0.10 inches in diameter.
 38. Thedevice of claim 31 wherein the matrix body has a width of less thanabout 0.10 inches in diameter.
 39. The device of claim 31 wherein thematrix body is configured as a rolled up sheet.
 40. The device of claim31 wherein the matrix body is configured as a button.
 41. The device ofclaim 31 wherein the matrix body is configured as a disc.
 42. The deviceof claim 31 wherein the matrix body is configured as a tube.
 43. Thedevice of claim 31 wherein the matrix body is configured of acombination of microspheres and fibers.
 44. The device of claim 33wherein the polymeric matrix body is made of a biostable materialselected from the group consisting of silicone, polyurethane, polyetherurethane, polyether urethane urea, polyamide, polyacetal, polyester,poly(ethylene-chlorotrifluoroethylene), poly tetrafluoroethylene(Teflon), styrene butadiene rubber, polyethylene, polypropylene,polyphenylene oxide-polystyrene, poly-a-chloro-p-xylene,polymethylpentene and polysulfone.
 45. The device of claim 31 furthercomprising a recovery tether attached to the matrix body.
 46. The deviceof claim 31 wherein the analgesic is an analgesic that acts on opioidpain receptors.
 47. The device of claim 46 wherein the analgesic thatacts on opioid pain receptors is selected from the group consisting ofmorphine, fentanyl, sufentanil, alfentanil, hydromorphone, meperidine,methadone, buprenorphine, DADL and butorphanol.
 48. The device of claim31 wherein the analgesic is an analgesic that acts on non-opioid painreceptors.
 49. The device of claim 46 wherein the analgesic that acts onnon-opioid pain receptors is selected from the group consisting ofketorolac, super oxide dismutase, baclofen, calcitonin, serotonin,vasoactive intestinal polypeptide, bombesin and omega-conopeptide. 50.The device of claim 46 wherein the analgesic that acts on non-opioidpain receptors is an alpha-2 adrenergic agonist.
 51. The device of claim48 wherein the alpha-2 adrenergic agonist is selected from the groupconsisting of clonidine, tizanidine, ST-91, medetomidine anddexmedetomidine.
 52. The device of claim 48 wherein the analgesic thatacts on non-opioid pain receptors is an NMDA receptor antagonist. 53.The device of claim 52 wherein the NMDA receptor antagonist is selectedfrom the group consisting of dexmethorphan, Ifenprodil and MK-801. 54.The device of claim 48 wherein the analgesic that acts on non-opioidpain receptors is a somatostatin analog.
 55. The device of claim 54wherein the somatostatin analog is selected from the group consisting ofOctreotide, Sandostatin, Vapreotide and Lanreotide.
 56. The device ofclaim 31 wherein the body is configured for ease of introduction to andremoval from the neuraxis of a body.
 57. The device of claim 31 whereinthe analgesic is present in the matrix in an amount of about 10% to 80%by weight.
 58. The device of claim 31 configured such that the analgesicis eluted at a sustained rate over the useful life of the device.
 59. Adevice for administering an analgesic at a sustained rate over a periodof time, the device being shaped, sized and adapted for administeringthe analgesic into the region of the neuraxis of the analgesic availablefor diffusion only therefrom in the animal environment into theneuraxis, wherein the analgesic is selected from the group consisting ofalpha-2 adrenergic receptor agonists, ketorolac, super oxide dismutase,and serotonin.
 60. A device for administering an analgesic at asustained rate over a period of time, the device being shaped, sized andadapted for administering the analgesic into the region of the neuraxisof an animal environment, the device comprising:a biostable polymericmatrix body containing an analgesic available for diffusion onlytherefrom in the animal environment into the neuraxis, wherein theanalgesic is selected from the group consisting of alpha-2 adrenergicreceptor agonists, ketorolac, super oxide dismutase, and serotonin; anda recovery tether attached to the body.
 61. A device for administeringan analgesic to an animal at a sustained rate over a period of time, thedevice being shaped, sized and adapted for administering the analgesicinto the region of the spinal column of the animal, the devicecomprising:a biostable polymeric hollow tube, the polymeric materialcapable of allowing a selected analgesic to diffuse only therefrom, thepolymeric hollow tube having opposed ends; the selected analgesic,loaded into the interior of the polymeric hollow tube, the analgesicavailable for diffusion only therefrom into the region of the spinalcolumn of the animal; and wherein the opposed ends of the polymerichollow tube are sealed with the selected analgesic inside the tube.